This invention relates to new 4-piperazinyl indole derivatives with 5-HT6 receptor affinity, and associated pharmaceutical compositions, methods for use as therapeutic agents, and methods of preparation thereof.
The actions of the neurotransmitter 5-hydroxytryptamine (5-HT) as a major modulatory neurotransmitter in the brain, are mediated through a number of receptor families termed 5-HT1, 5-HT2, 5- HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Based on a high level of 5-HT6 receptor mRNA in the brain, it has been stated that the 5-HT6 receptor may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT6 receptor selective ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson""s disease, Huntington""s disease, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, migraine, Alzheimer""s disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder. (See for ex. B. L. Roth et al., J. Pharmacol. Exp. Ther., 268, pages 1403-14120 (1994), D. R. Sibley et al., Mol. Pharmacol., 43, 320-327 (1993), A. J. Sleight et al, Neurotransmission, 11, 1-5 (1995), and A. J. Sleight et al. Serotonin ID Research Alert, 1997, 2 (3), 115-8).
Furthermore, the effect of 5-HT6 antagonist and 5-HT6 antisense oligonucleotides to reduce food intake in rats has been reported (Br J Pharmac. 1999 Suppl 126, page 66 and J Psychopharmacol Suppl A64 1997, page 255).
This invention relates to compounds comprising Formula I: 
wherein:
R1 is selected from hydrogen, halo, haloalkyl, and C1-6-alkyl;
R2 is selected from hydrogen, C1-6-alkyl, C1-6-alkoxy, and C1-6-alkylthio;
R3 is xe2x80x94SO2xe2x80x94Ar, and Ar is selected from aryl and heteroaryl, optionally substituted with one or more substitutents selected from lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, hydroxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, alkylsulfonyl, haloalkylsulfonyl, aminosulfonyl, and sulfonylamino;
R4 is selected from hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylthio, trifluoromethyl, cyano, and acyl; and
R5 is selected from hydrogen, C1-6-alkyl and benzyl; or individual isomers, racemic or non racemic mixtures of isomers, prodrugs, or pharmaceutically acceptable salts or solvates thereof.
In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier.
In another aspect, this invention relates to a method of treatment of a disease in a mammal treatable by administration of compound of Formula I having a selective affinity to 5-HT6 receptor, in particular a method of treatment in a subject having a disease state comprising Alzheimer""s disease, central nervous disorders, such as for example, psychoses, schizophrenia, manic depressions, neurological disorders, Parkinson""s disease, amyotrophic lateral sclerosis and Huntington""s disease. In another aspect, this invention relates to a method of treatment in a subject having a gastrointestinal disease comprising functional bowel disorder. Other disease states alleviated by 5-HT6 agonists, and therefore by the compounds of Formula I, are gastrointestinal diseases comprising irritable bowel syndrome (IBS), and obesity.
In a preferred embodiment, the invention further relates to a process which comprises:
treatment of a compound of formula f 
wherein P is a protective group and R1, R2 and R4 are as defined herein, with an arylsulfonyl halide of Formula Arxe2x80x94SO2-Hal wherein Hal is a halogen; followed by deprotection to provide a compound of general Formula I: 